Project Summary Malaria remains a significant global health problem that would greatly benefit from the development of a vaccine. Protection against clinical disease could be achieved by eliciting a protective immune response against the blood stage of the malaria parasite. However, only a very limited number of vaccine candidates are currently being studied. One approach to uncover novel potential vaccine targets is to analyze protective anti- malaria immunity in response to natural infection. Natural Plasmodium falciparum infections induce antibody responses that target the blood stage of this parasite. With repeated exposures, these responses accumulate to a level that protects against symptomatic disease. While dissection of the antibody specificities responsible for disease protection has taught us much about protective B-cell immunity, a large fraction of potential B-cell antigens has thus far remained unexplored. In this project, I propose to develop an unbiased platform to isolate antibodies that interfere with parasite replication during the malaria blood stage. In specific Aim 1, I will select individuals living in malaria-endemic regions who have developed protective immunity against the parasite and screen their serum for the capacity to bind to merozoites. A subset of individuals with serum reactivity against diverse parasite isolates will be selected for further study. In specific Aim 2, memory B cells will be isolated from these subjects and will be individually cultured to produce antibodies. These monoclonal antibodies will be screened for the ability to bind merozoites and induce opsonic phagocytosis. In specific Aim 3, antibodies with strong anti-parasite activity will be cloned and expressed as human IgG for further characterization. In a follow-up study, these antibodies can be used for the identification of novel vaccine antigens. This antibody discovery platform is designed to identify the types of antibodies that should be elicited by a protective vaccine: antibodies with broad and potent anti-malaria activity. The methodology developed in this project is uniquely based on screening of antibodies in functional assays and is thus fundamentally different from alternative methods for dissecting B-cell immunity that have thus far been used in the field. This approach therefore has the potential to discover novel antibodies and antibody specificities. Ultimately, the results of this project will provide much-needed insight into protective anti-malaria immunity and will accelerate vaccine design. !